The long-term goal of the principal investigator's research is an improved understanding of glucose metabolism in normal and diabetic man and ultimately improved therapy of diabetes mellitus. The objective of the proposed research is to define the roles of insulin and glucose in regulating hepatic and extrahepatic glucose metabolism in both the postabsorptive and postprandial states. Isotope dilution techniques will be central to these studies. Therefore, prior to initiation of these protocols, the effects of hyperinsulinemia, hyperglycemia, and diabetes mellitus on "futile" cycling, will be critically examined. Since "futile" cycling of glucose can alter the validity of these techniques, these studies will be essential for interpretation of the results of the proposed research as well as those of all other investigators using these isotopes in their own research. Subsequently in an effort to establish a firm scientific basis for the design of appropriate treatment of diabetes mellitus, the effects of diabetes mellitus on hepatic and extrahepatic processing of carbohydrate meals will be defined and the ability of intensive insulin therapy to restore this process towards normal will be determined. Since diabetes mellitus is characterized by both insulin resistance and growth hormone excess, the influence of growth hormone on hepatic and extrahepatic glucose metabolism and meal disposition will be examined. In order to examine the role of insulin resistance in the pathogenesis of postprandial glucose intolerance in both NIDDM and IDDM, a method of assessing insulin action under conditions that mimic those normally present during meal disposition (i.e., continuously changing circulating insulin concentrations) will be developed. This method will be used to measure hepatic and extrahepatic responses to insulin in diabetic patients. The results obtained will be compared to those observed when identical amounts of insulin are given as a several hour constant insulin infusion using the traditional but unphysiologic hyperinsulinemic-euglycemic clamp. Completion of the proposed protocols hopefully will provide a better understanding of the mechanisms of glucose intolerance in diabetes mellitus.